Compared with control brain tissue, postmortem brain from Alzheimer disease (AD) patients showed 50% decreases in mRNA levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunits I and III, and in mRNA levels of NADH- dehydrogenase subunit 1, nuclear DNA (nDNA)-encoded COX subunit IV, and ATPase-beta. There was no difference in mRNA levels of the mt-DNA encoded 12S rRNA or of the nDNA-encoded lactate dehydrogenase subunit B or beta actin. Results suggested physiological, and potentially reversible, down-regulation of brain oxidative-phosphorylation in AD. Neurofibrillary tangles in postmortem brain samples from patients with AD are associated with decreased neuronal levels of a molecular marker of neuronal energy metabolism, COX subunit III mRNA. Even tangle-free neurons showed decreased levels of this marker compared with tangle-free neurons from control brain, suggesting early synaptic dysfunction in AD. Neuritic plaques are another pathological hallmark of AD. Neurons close to neuritic plaques showed no decrease in COX III mRNA or COX enzyme activity compared with more distant neurons. Therefore, neuritic plaques do not contribute to reduced neuronal energy metabolism in AD.